AU2013308907B2 - Anti-prolactin receptor antibody formulations - Google Patents
Anti-prolactin receptor antibody formulations Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
Abstract
Provided are a wide concentration range, especially high concentration, substantially salt-free anti-prolactin receptor antibody formulations that are substantially isosmotic and of low viscosity.
Description
A61K 39/395 (2006.01)
(21) | Application No: 2013308907 (22) | Date of Filing: 2013.08.28 | |
(87) | WIPO No: WO14/036076 | ||
(30) | Priority Data | ||
(31) | Number 61/695,949 13/842,906 | (32) Date 2012.08.31 2013.03.15 | (33) Country US US |
(43) (44) | Publication Date: Accepted Journal Date: | 2014.03.06 2018.04.19 | |
(71) | Applicant(s) Bayer Healthcare LLC | ||
(72) | Inventor(s) Ma, Xinghang;Xiang, Jun;Niu, Jianjie | ||
(74) | Agent / Attorney Davies Collison Cave Pty Ltd, Level 14 255 Elizabeth Street, Sydney, NSW, 2000, AU |
(56) Related Art
EP 2 332 995 A1 WO 2011/104381 A2 US 7 ,422,899 B2 US 7,867,493 B2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization
International Bureau (43) International Publication Date 6 March 2014 (06.03.2014)
(10) International Publication Number
WIPOIPCT
WO 2014/036076 Al (51) International Patent Classification:
A61K39/395 (2006.01) A61P 5/00 (2006.01)
C07K16/28 (2006.01) (21) International Application Number:
PCT/US2013/056976 (22) International Filing Date:
August 2013 (28.08.2013) (25) Filing Uanguage: English (26) Publication Uanguage: English (30) Priority Data:
61/695,949 31 August 2012 (31.08.2012) US
13/842,906 15 March 2013 (15.03.2013) US (71) Applicant: BAYER HEAUTHCARE UUC [US/US]; 100 Bayer Boulevard, Whippany, New Jersey 07981-0915 (US).
(72) Inventors: MA, Xinghang; 2511 Valentano Drive, Dublin, CA 94568 (US). XIANG, Jun; 1382 Contra Costa __ Boulevard #65, Pleasant Hill, CA 94523 (US). NIU, Ji~~ anjie; 21949 Pheasant Woods Drive, Castro Valley, CA = 94552 (US).
(74) Agent: KOWAUCHYK, Katherine M.; Merchant & Gould P.C., P.O. Box 2903, Minneapolis, MN 55402-0903 = (US).
(81) Designated States (unless otherwise indicated, for every kind of national protection available)·. AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR,
KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
(84) Designated States (unless otherwise indicated, for every kind of regional protection available)·. ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG).
Published:
— with international search report (Art. 21(3)) — with sequence listing part of description (Rule 5.2(a))
WO 2014/036076 Al (54) Title: ANTI-PROLACTIN RECEPTOR ANTIBODY FORMULATIONS (57) Abstract: Provided are a wide concentration range, especially high concentration, substantially salt-free anti-prolactin receptor antibody formulations that are substantially isosmotic and of low viscosity.
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PCT/US2013/056976
ANTI-PROLACTIN RECEPTOR ANTIBODY FORMULATIONS
This application is being filed on 28 August 2013, as a PCT International patent application, and claims priority to U.S. Provisional Patent Application No.
61/695,949, filed August 31, 2012, and U.S. Patent Application No. 13/842,906, filed March 15, 2013, the disclosures of which are hereby incorporated by reference herein in their entirety.
BACKGROUND
The present disclosure relates generally to a wide concentration range of 10 anti-prolactin receptor antibody formulations that are substantially isosmotic and of low viscosity, including formulations that are useful for subcutaneous and general injection administration.
Prolactin (PRL) is a polypeptide hormone composed of 199 amino acids. PRL belongs to the growth hormone (GH), placental lactogen (PL) family of polypeptide hormones and is synthesized in lactotroph cells of the pituitary and in several extrapituitary tissues such as lymphocytes, mammary epithelial cells, the myometrium, and the prostate. Two different promoters regulate pituitary and extrapituitary PRL synthesis (BioEssays 28:1051 -1055 (2006)).
PRL binds to the PRL receptor (PRLR), a single transmembrane receptor belonging to the class 1 cytokine receptor superfamily (Endocrine Reviews 19:225268 (1998)). PRLR exists in three different isoforms, the short, the long, and the intermediate form that can be distinguished by the length of their cytoplasmic tails. Upon ligand binding, a sequential process leads to PRLR activation. PRL interacts via its binding site 1 with one PRLR molecule and then attracts via its binding site 2 a second receptor molecule leading to an active dimer of PRLRs.
PRLR dimerization leads to the predominant activation of the JAK/STAT (Janus Kinase/Signal transducers and activators of transcription) pathway. Upon receptor dimerization, JAKs (predominantly JAK2) associated with the receptor, transphosphorylate and activate each other. In addition the PRLR is also phosphorylated and can bind to SH2-domain containing proteins such as STATs. 1
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Receptor bound STATs are subsequently phosphorylated, dissociate from the receptor and translocate to the nucleus where they stimulate transcription of target genes. In addition, activation of the Ras-Raf-MAPK pathway and activation of the cytoplasmic src kinase by PRLRs have been described (for review Endocrine
Reviews 19: 225-268 (1998)).
The role of PRLR-mediated signalling has been investigated in the context of the benign disease endometriosis. In one study the expression pattern of the PRLR in endometriotic samples and eutopic endometrium from endometriosis patients was analysed (Acta Obstet Gynecol Scand 81/5-10, 2002) during the mid-late proliferative phase of the menstrual cycle. It was demonstrated that the PRLR mRNA was present in the eutopic endometrium in 79% of the analysed endometriosis patients, whereas it was absent in the endometriotic lesions in 86% of the endometriosis patients. These data suggested a possible differential regulation of PRLR expression between normal and endometriotic tissue. However, from these expression data it cannot be concluded that inhibition of the PRLR might represent a suitable endometriosis therapy - especially since the PRLR was not found to be expressed in the endometriotic lesions (Acta Obstet Gynecol Scand 81:5-10 (2002)).
Antibodies that are directed against prolactin receptor (PRLR), including anti-PRLR monoclonal antibodies (aPRLR mAbs), are being developed in an effort to block PRLR function. One such aPRLR mAb is an IgG2 anti-PRLR mAb that is being developed for the non-hormonal treatment of endometriosis patients.
Antibodies may be administrated to patients via intravenous, intramuscular, and/or subcutaneous injection. To ensure patient compliance, it is desirable that intramuscular and subcutaneous injection dosage forms be isotonic and include small injection volumes (<2 ml per injection site). To reduce injection volume, and to provide an effective dose, antibodies are often administered with a wide concentration range, from 1 mg/ml to 150 mg/mL, including high concentrations within the range of 20 mg/ml to 150 mg/ml.
While both liquid and lyophilized dosage forms are used for currently marketed antibody drug products, lyophilized forms are more frequently used for 2
2013308907 21 Dec 2017 antibody drug products having high protein concentrations. A high concentration antibody formulation may present many challenges in formulation development, especially for liquid formulation. For formulations in which the antibody concentration is near its apparent solubility limit, phase separation can occur through precipitation, gelation, and/or crystallization. At high protein concentration, the stability of an antibody can become problematic due to the formation of soluble and insoluble protein-protein aggregates. Highly concentrated antibody formulations are frequently highly viscous, which presents difficulties for processing, such as ultrafiltration and sterile filtration, and for injection of the dosage solution. And at high antibody concentrations, which are desirable for formulations intended for intramuscular or subcutaneous administration, proportionally high concentrations of stabilizers, such as sucrose and sodium chloride, are required to achieve long-term protein stability. The resulting hypertonic solutions often cause injection pain due to tissue damage. Therefore, it is often desirable to balance the amount of stabilizers for stability and osmolality of the high protein concentration formulation.
SUMMARY
In a first aspect the present invention provides an anti-PRLR antibody formulation, comprising:
a. 10 mM to 70 mM histidine;
b. 50 ppm to 300 ppm polysorbate 80;
c. 34 mM to 292 mM sucrose; and
d. 1 mg/ml to 150 mg/ml of an anti-PRLR antibody;
wherein said anti-PRLR antibody formulation has a pH ranging from pH 5.0 to pH 6.5, and wherein the formulation comprises substantially no salt other than an organic or inorganic salt that buffers said formulation.
In a second aspect the present invention provides a method for the nonhormonal treatment of endometriosis, the method comprising administering a subject in need thereof a therapeutically effective amount of an anti-PRLR antibody formulation according to the first aspect, wherein the formulation is administered intravenously, subcutaneously or intramuscularly.
2013308907 21 Dec 2017
In a third aspect the present invention provides use of an anti-PRLR antibody formulation according to the first aspect in the manufacture of a medicament for the non-hormonal treatment of endometriosis.
The present disclosure provides liquid and lyophilized anti-PRLR antibody 5 formulations with a wide range of anti-PRLR antibody concentrations, which are substantially isotonic and low viscosity and that contain substantially no salt other than an organic salt or an inorganic salt that is used to buffer the formulation.
The anti-PRLR antibody formulations presented herein contain from about 0 mM to about 70 mM histidine; from about 50 ppm to about 300 ppm of a non-ionic surfactant such as, for example, polysorbate (Tween®) 80 and/or polysorbate (Tween®) 20; from about 34 mM to about 292 mM of a sugar or sugar alcohol such as, for example, mannitol, dextrose, glucose, trehalose, and/or sucrose; from about 0 mM to about 50 mM arginine; from about 0 mM to about 50 mM lysine; from about 0 mM to about 270 mM glycine or alanine; from about 0 mM to about 10 mM methionine; and from about 1 mg/ml to about 150 mg/ml of an anti-PRLR antibody, including an aPRLR-specific IgG2 monoclonal antibody (mAb) at a pH from about pH 5.0 to about pH 6.5.
3A
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Each of the presently disclosed antibody formulations contains substantially no salt other than an organic salt or an inorganic salt that is used to buffer the formulation. This permits the addition of alternative stabilizers to maintain the isosmoticity of the formulation (i.e., osmolality ranging from about 240 mmol/kg to about 380 mmol/kg), which thereby promotes a higher degree of patient compliance.
Each of the presently disclosed antibody formulations has a low viscosity ranging from about 1 to about 8 mPa-S at 22°C-23°C, which promotes ease of processing such as, for example, improved ultrafiltration and sterile filtration as well as injection of the antibody formulation through a syringe needle during administration.
The formulations disclosed herein stabilize antibodies, in particular antiPRLR antibodies including anti-PRLR IgG2 antibodies, at high protein concentrations in liquid form or in lyophilized form.
DESCRIPTION OF VARIOUS EMBODIMENTS
As described above, the present disclosure provides anti-PRLR antibody formulations that stabilize the anti-PRLR antibody in a wide range of concentrations in liquid form or in lyophilized form at intended storage conditions. The formulations described herein include one or more pharmaceutically acceptable excipients or stabilizers, and are contained in buffered media at a suitable pH and are substantially isosmotic with physiological fluids. For systemic administration, injection is one possible route of administration, including intramuscular, intravenous, intraperitoneal, and subcutaneous for injection.
Because of their low viscosity, the presently disclosed anti-PRLR antibody formulations can be conveniently processed via, for example, ultrafiltration and sterile filtration and can be administered to a patient via injection, including both intravenous and subcutaneous injection. Moreover, because they are substantially isosmotic, the presently disclosed anti-PRLR antibody formulations reduce tissue damage or other adverse physiologic effects and thereby achieving favorable patient tolerance and increased patient compliance.
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The formulations described herein are characterized by the substantial absence of added salt other than an organic salt or an inorganic salt that is used to buffer the formulation, which provides the flexibility for increasing the concentrations of other stabilizers, such as sucrose, while maintaining the osmolality of the formulation for improved in vivo tolerability and, consequently, increased patient compliance. Moreover, the low viscosity of the presently described formulations permits convenient processing, including ultrafiltration and sterile filtration, and injection of the drug product solution through the needle.
For the purpose of interpreting this specification, the following definitions 10 will apply. In the event that any definition set forth below conflicts with the usage of that word in any other document, including any document Incorporated herein by reference, the definition set forth below shall always control for purposes of interpreting this specification and its associated claims unless a contrary meaning is clearly intended (for example in the document where the term is originally used).
Whenever appropriate, terms used in the singular also will include the plural and vice versa. The use of “a” herein means “one or more” unless stated otherwise or where the use of “one or more” is clearly inappropriate. The use of or means and/or unless stated otherwise. The use of “comprise,” “comprises,” “comprising,” “include,” “includes,” and “including” are interchangeable and not intended to be limiting. The term “such as” also is not intended to be limiting. For example, the term “including” shall mean “including, but not limited to.” Furthermore, where the description of one or more embodiments uses the term “comprising,” those skilled in the art would understand that, in some specific instances, the embodiment or embodiments can be alternatively described using the language “consisting essentially of’ and/or “consisting of.”
As used herein, the term “viscosity” refers to the resistance of a liquid formulation to flow, such as when injected through a syringe needle during administration to a patient. Viscosity measurements can be done by a cone and plate technique with a Peltier element set at a defined temperature, such as 22°C-23°C as described herein. Typically, a well-defined shear stress gradient is applied to the liquid formulation and the resulting shear rate is measured. The viscosity is the ratio 5
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PCT/US2013/056976 of the shear stress to the shear rate. As used herein, viscosity is expressed in units of mPa-S at 22°C-23°C wherein 1 mPa-S = 1 cP. The high concentration, low viscosity, substantially isosmotic formulations disclosed herein are typically characterized by having a viscosity ranging from 1 to 8 mPa-S at 22 °C-23°C.
As used herein, the term “osmolality” refers to a measure of solute concentration, defined as the number of mmole of solute per kg of solution. A desired level of osmolality can be achieved by the addition of one or more stabilizer such as a sugar or a sugar alcohol including mannitol, dextrose, glucose, trehalose, and/or sucrose. Additional stabilizers that are suitable for providing osmolality are described in references such as the handbook of Pharmaceutical Excipients (Fourth Edition, Royal Pharmaceutical Society of Great Britain, Science & Practice Publishers) or Remingtons: The Science and Practice of Pharmacy (Nineteenth Edition, Mack Publishing Company).
As used herein, the term “about” refers to +/-10% of the unit value provided.
As used herein, the term “substantially” refers to the qualitative condition of exhibiting a total or approximate degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, achieve or avoid an absolute result because of the many variables that affect testing, production, and storage of biological and chemical compositions and materials, and because of the inherent error in the instruments and equipment used in the testing, production, and storage of biological and chemical compositions and materials. The term substantially is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
As used herein, the terms “isosmotic” and “isotonic” are used interchangeably with the terms “substantially isosmotic,” and “substantially isotonic” and refer to formulations characterized by having an osmotic pressure that is the same as or at least substantially equivalent to the osmotic pressure of another solution, which is achieved by formulations wherein the total concentration of solutes, including both permeable and impermeable solutes, in the formulation are the same as or at least substantially equivalent to the total number of solutes in another solution. Thus, while it will be 6
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PCT/US2013/056976 appreciated by those of skill in the art that “isosmotic” and “isotonic” formulations that are used for in vivo administration generally have an osmolality ranging from about 270 mmol/kg to about 310 mmol/kg, in the context of the high concentration, low viscosity formulations of the present disclosure, the terms “isosmotic,” “isotonic,” “substantially isosmotic,” and “substantially isotonic” are used interchangeably to refer to formulations having an osmolality ranging from about 240 mmol/kg to about 380 mmol/kg, or from about 270 mmol/kg to about 370 mmol/kg, or from about 300 mmol/kg to about 330 mmol/kg.
The presently disclosed high concentration, low viscosity, substantially 10 isosmotic anti-PRLR antibody formulations contain from about 0 mM to about 70 mM histidine; from about 50 ppm to about 300 ppm of a non-ionic surfactant such as, for example, polysorbate (Tween®) 80 and/or polysorbate (Tween®) 20; from about 34 mM to about 292 mM of a sugar or sugar alcohol, such as, for example, mannitol, dextrose, glucose, trehalose, and/or sucrose; from about 0 mM to about 50 mM arginine; from about 0 mM to about 50 mM lysine; from about 0 mM to about 270 mM glycine or alanine; from about 0 mM to about 10 mM methionine; and from about 1 mg/ml to about 150 mg/ml of an anti-PRLR antibody at a pH from about pH 5.0 to about pH 6.5. The formulations disclosed herein exhibit a viscosity ranging from about 1 to about 8 mPa-S at 22°C-23°C and osmolality ranging from about 240 to about 380 mmol/kg.
In these formulations, histidine is a buffer agent, which can be used to maintain the formulation pH from about pH 5.0 to about pH 6.5, or from about pH 5.5 to about pH 6.0, such as about pH 5.0, about pH 5.5, about pH 6.0, or about pH 6.5.
Sugars or sugar alcohol, such as mannitol, dextrose, glucose, trehalose, and/or 25 sucrose, are used separately or in combination both as cryo-protectants and a stabilizer the anti-PRLR antibody in liquid formulations as well as during lyophilization.
Non-ionic surfactants such as polysorbates, including polysorbate 20 and polysorbate 80; polyoxamers, including poloxamer 184 and 188; pluronic® polyols;
and other ethylene/polypropylene block polymers, stabilize the anti-PRLR antibody 7
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PCT/US2013/056976 during processing and storage by reducing interfacial interaction and prevent antibody from adsorption.
Arginine is a protein solubilizer and also a stabilizer that reduces antibody and other protein aggregation, such as anti-PRLR antibody aggregation, and other possible degradation. Methionine is an antioxidant that prevents antibody oxidation during processing and storage.
Sugars and inorganic salts are commonly used as protein stabilizers; however, both sugars and inorganic salts are also effective tonicity agents. If a formulation requires a high concentration of one or more sugars to stabilize an anti10 PRLR antibody, the inorganic salt concentration should be zero or kept very low in order to maintain the formulation’s osmolality such that injection pain is reduced upon administration.
As used herein, the term “salt” refers to inorganic salts, which include sodium chloride (NaCl), sodium sulfate (Na2SC>4), sodium thiocyanate (NaSCN), magnesium chloride (MgCl), magnesium sulfate (MgSCfi), ammonium thiocyanate (NH4SCN), ammonium sulfate ((NH4)2SO4), ammonium chloride (NH4CI), calcium chloride (CaCl2), calcium sulfate (CaSO4), zinc chloride (ZnCl2) and the like, or combinations thereof. The anti-PRLR antibody formulations disclosed herein are characterized by a substantial absence of added salt and are, therefore, referred to herein as salt-free antibody formulations. It will be understood by those of skill in the art that the presence of inorganic salts within the presently disclosed formulations that are introduced by pH adjustment are not considered to be added salts. Such inorganic salts when introduced by pH adjustments, if present in a formulation according to the present disclosure, should not exceed a concentration of about 2 mM.
As used herein, the term “surfactant” includes non-ionic surfactants including, without limitation, polysorbates, such as polysorbate 20 or 80, and the polyoxamers, such as poloxamer 184 or 188, pluronic® polyols, and other ethylene/polypropylene block polymers. Amounts of surfactants effective to provide stable high concentration anti-PRLR antibody formulations are usually in the
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PCT/US2013/056976 range of 50 ppm to 300 ppm. The use of non-ionic surfactants permits the formulations to be exposed to shear and surface stresses without causing denaturation of the anti-PRLR antibody, and also reduce the adsorption on the surfaces during processing and storage. The formulations disclosed herein include, without limitation, formulations having one or more non-ionic surfactant(s) including, for example, one or more polysorbate(s), such as polysorbate 20 or 80; one or more polyoxamers, such as poloxamer 184 or 188; pluronic® polyols; and/or one or more ethylene/polypropylene block polymer(s). Exemplified herein are formulations having a polysorbate, such as polysorbate 20 (Tween® 20) or polysorbate 80 (Tween® 80).
As used herein, the term “antibody” refers to a class of proteins that are generally known as immunoglobulins. Antibodies include full-length monoclonal antibodies (mAh), such as IgG2 monoclonal antibodies, which include immunoglobulin Fc regions. The term antibody also includes bispecific antibodies, diabodies, single-chain molecules, and antibody fragments such as Fab, F(ab')2, and Fv.
As used herein, the term “anti-PRLR antibody” refers to an antibody having binding specificity against the human PRLR protein as well as fragments and variants of the human PRLR protein. Anti-PRLR antibodies presented herein can be
IgG2 antibodies and include anti-PRLR IgG2 monoclonal antibodies, such as chimeric, humanized, and fully-human anti-PRLR IgG2 monoclonal antibodies. Anti-PRLR monoclonal antibodies, including full-length antibodies and antigen binding fragments and variants thereof, that are suitable for use in the formulations disclosed herein are presented in PCT Patent Publication NOs. WO/2011/069799,
WO/2011/069798, WO/2011/069797, WO/2011/069796, WO/2011/069795, and
WO/2011/069794, each of which are incorporated by reference herein in their entirety.
“Monoclonal antibodies” are characterized by having specificity for a single antigenic determinant. Monoclonal antibodies can, for example, be made by the hybridoma method described by Kohler and Milstein, Nature 256:495 (1975) or by recombinant DNA methods such as those described in U.S. Patent No. 4,816,567. 9
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Monoclonal antibodies can also be isolated from phage display libraries using the techniques such as those described in Clackson et al., Nature 352:624-628 (1991) and Marks et al., J. Mol. Biol. 222:581-597 (1991).
Monoclonal antibodies include “chimeric monoclonal antibodies” wherein a 5 portion of a heavy and/or light chain includes sequences from antibodies derived from one species, while the remainder of the antibody, including the Fc region, includes sequences from antibodies derived from a second species, and the second species may be human. See, e.g., U.S. Patent No. 4,816,567 and Morrison et al.,
Proc. Natl. Acad. Sci. USA 84:6851-6855 (1984).
Monoclonal antibodies also include “humanized monoclonal antibodies” wherein one or more complementarity determining region (CDR) from a heavy and/or light chain sequence from antibodies derived from one species replace one or more CDR from a heavy and/or light chain sequence from antibodies derived from a second species, and the second species may be human. The process of humanization is usually applied to monoclonal antibodies developed for administration to humans. See, e.g., Riechmann et al., Nature 332(6162):323-27 (1988) and Queen et al., Proc. Natl. Acad. Sci. USA 86(24):10029-33 (1989).
Monoclonal antibodies also include “fully-human monoclonal antibodies” wherein the entire heavy and light chain sequences are derived from human antibody sequences. Fully-human monoclonal antibodies can be generated by phage display technologies and can be isolated from mice that have been genetically engineered to express the human antibody repertoire. See, e.g., McCafferty et al., Nature 348(6301):552-554 (1990), Marks et al., J. Mol. Biol. 222(3):581-597 (1991), and Carmen and Jermutus, Brief Funct. Genomic Proteomic 1(2):189-203 (2002).
As used herein, the term “Pharmaceutically effective amount” of an antiPRLR antibody formulation refers to an amount of the formulation that provides therapeutic effect in an administration regimen. The high concentration anti-PRLR antibody formulations disclosed herein typically include an anti-PRLR antibody at a concentration ranging from about 1 mg/ml to about 150 mg/ml, or from about 2 mg/ml to about 120 mg/ml, or from about 5 mg/ml to about 100 mg/ml, or from
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PCT/US2013/056976 about 7.5 mg/ml to about 60 mg/ml. Within some aspects the concentration of antiPRLR antibody within these formulations is about 2 mg/ml, or about 7.5 mg/ml, or about 20 mg/ml, or about 50 mg/ml, or about 60 mg/ml. Such formulations are typically administered in a volume of less than about 2 ml, or about 1.5 ml, or about
1 ml, or about 0.5 ml per injection site for subcutaneous injection.
Within certain aspects, the anti-PRLR antibody formulation contains about 30 mM histidine, about 100 ppm polysorbate 80, about 292 mM sucrose, about 20 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about
10 mM to about 50 mM arginine.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 80 ppm polysorbate 80, about 234 mM sucrose, about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 30 mM to about 50 mM arginine.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 75 ppm polysorbate 80, about 234 sucrose, about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 30 mM to about 50 mM arginine.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 75 ppm polysorbate 80, about 88 mM sucrose, about 133 mM glycine, about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 10 mM to about 50 mM arginine.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 75 ppm polysorbate 20, about 88 mM sucrose, about 133 mM glycine, about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to
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PCT/US2013/056976 about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 10 mM to about 50 mM arginine.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 200 ppm polysorbate 20, about 88 mM sucrose, about 133 mM glycine, about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 10 mM to about 50 mM arginine.
Within other aspects, the anti-PRLR antibody formulation contains about 70 mM histidine, about 80 ppm polysorbate 80, about 200 mM sucrose, about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 10 mM to about 50 mM arginine.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 80 ppm polysorbate 80, about 292 mM sucrose, about 10 mM arginine, about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 0 mM to about 10 mM methionine.
Within other aspects, the anti-PRLR antibody formulation contains about 70 mM histidine, about 80 ppm polysorbate 80, about 176 mM sucrose, about 133 mM glycine, about 30 mM lysine, about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 75 ppm about polysorbate 80, about 234 mM sucrose, about 30 mM arginine, about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH
5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 0 mM to 10 mM methionine.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 80 ppm about polysorbate 80, about 234 mM sucrose, about 20 mM arginine, about 150 mg/ml anti-PRLR antibody at a pH ranging from about pH
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5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 0 mM to 10 mM methionine.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 80 ppm about polysorbate 80, about 205 mM sucrose, about 20 mM arginine, about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 0 mM to 10 mM methionine.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 80 ppm about polysorbate 80, about 205 mM sucrose, about 20 mM arginine, about 2 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 0 mM to 10 mM methionine.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 80 ppm about polysorbate 80, about 205 sucrose, about 20 mM arginine, about 1 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 0 mM to 10 mM methionine.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 75 ppm about polysorbate 80, about 205 trehalose, about 20 mM arginine, about 2 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 0 mM to 10 mM methionine.Within other aspects, the antiPRLR antibody formulation contains about 10 mM histidine, about 75 ppm about polysorbate 80, about 205 trehalose, about 20 mM arginine, about 60 mg/ml anti25 PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibody formulation also contains from about 0 mM to 10 mM methionine.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 234 mM sucrose, about 80 ppm polysorbate 80, about 30 mM
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Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 234 mM sucrose, about 80 ppm polysorbate 80, about 30 mM arginine, about 5 mM methionine, about 60 mg/mL anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5, such as pH 5.5.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 234 mM sucrose, about 75 ppm Tween 80, about 30 mM arginine, about 10 mM methionine, about 60 mg/mL anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5, such as pH 5.5.
Within other aspects, the anti-PRLR antibody formulation contains about 10 mM histidine, about 263 mM sucrose, about 80 ppm polysorbate 80, about 60 mg/mL anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5, such as pH 6.0.
Thus, the present disclosure provides anti-PRLR mAh formulations, including anti-PRLR IgG2 mAb formulations, wherein the anit-PRLR mAh is soluble at high protein concentrations. The anti-PRLR mAh in the formulations disclosed herein remain soluble at concentrations of between about 1 mg/ml to about 150 mg/ml and remain stable under isosmotic storage conditions and exhibit reduced viscosity as compared to currently available antibody formulations.
The anti-PRLR antibody having a light chain comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 7 is an IgG2 antibody that blocks prolactin receptor (PRLR). AntiPRLR antibodies can prevent the onset or progression of endometriosis by blocking
PRLR, thereby overcoming deficiencies in endometrial pathways. The high concentration, salt free anti-PRLR antibody formulations presented herein can be administrated to the patients via intravenous injection or subcutaneous injection or other injection routes.
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As part of the present disclosure, stability of anti-PRLR antibodies is affected by excipients. The stability of anti-PRLR antibody increases with the decrease of NaCl concentrations in the pH range defined. In addition, positively charged amino acids, such as arginine and lysine, can improve the stability anti-PRLR antibody and that pH greatly affects anti-PRLR antibody aggregation. The aggregation of antibody solutions increases with increases in pH. The optimal pH for stabilizing the antiPRLR antibodies presented herein ranges from about pH 5.0 to about pH 6.5 or from about pH 5.5 to about pH 6.0 such as about pH 5.0, about pH 5.5, about pH 6.0, or about pH 6.5.
Provided herein are anti-PRLR antibody formulations wherein the anti-PRLR antibodies include IgG2 antibodies, including human IgG2 monoclonal anti-PRLR antibodies having a light chain sequence and a heavy chain sequence presented in one or more of PCT Patent Publication NOs. WO/2011/069799, WO/2011/069798, WO/2011/069797, WO/2011/069796, WO/2011/069795, and WO/2011/069794.
Antibodies that may be suitably employed in the anti-PRLR antibody formulations described herein are exemplified by the Mat3-hIgG2 antibody presented in Table 1, which was obtained from the Bioinvent Phage Display library (Lund, Sweden) and subsequently germlined and sequence-optimized for affinity, activity, species cross-reactivity, and manufacturability.
The Fab part comprises a lambda light chain (VL: DPL3 germline; CL: Mcg/Kem-/Oz- isotype) and a heavy chain VH DP47-germline framework region. The antibody was reformatted into a human IgG2 of the IgG2m (n-) heavychain allotype lacking the C-terminal lysine. A potential deamidation site is present in CDR3 at amino acid position 98 of the light chain and was left unchanged in this antibody.
The standard N-glycosylation site of IgG2 is present at N294 of the heavy chain.
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Table 1
Heavy and Light Chain Sequences of Exemplary Human Anti-PRLR IgG2
Monoclonal Antibody Mat3-hIgG2
Sequence Identifier | Portion of Antibody Chain | Amino Acid Sequence (NHj-COOH) |
SEQ ID NO: 1 | Light Chain, Full-length | QSVLTQPPSA SGTPGQRVTI SCTGSSSNIG AGYWHWYQQ LPGTAPKLLI YRNNQRPSGV PDRFSGSKSG TSASLAISGL. RSEDEADYYC AAWDDSLNGW LFGGGTKLTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT VAWKADSSPV KAGVETTTPS KQSNNKYAAS SYLSLTPEQW KSHRSYSCQV THEGSTVEKT VAPTECS |
SEQ ID NO: 2 | Light Chain, Variable Domain | QSVLTQPPSA SGTPGQRVTI SCTGSSSNIG AGYWHWYQQ LPGTAPKLLI YRNNQRPSGV PDRFSGSKSG TSASLAISGL RSEDEADYYC AAWDDSLNGW LFGGGTKLTV LGQ |
SEQ ID NO: 3 | Light Chain, Variable Domain, CDR1 | SCTGSSSNIG AGYWH |
SEQ ID NO: 4 | Light Chain, Variable Domain, CDR2 | RNNQRPS |
SEQ ID NO: 5 | Light Chain, Variable Domain, CDR3 | CAAWDDSLNG WL |
SEQ ID NO: 6 | Light Chain, Constant Domain | PKAAPSVTLF PPSSEELQAN KATLVCLISD FYPGAVTVAW KADSSPVKAG VETTTPSKQS NNKYAASSYL SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS |
SEQ ID NO: 7 | Heavy Chain, Full-length | EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYWMHWVRQA PGKGLEWVSD IARLSSYTNY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARGL DARRMDYWGQ GTLVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSWTVP SSNFGTQTYT CNVDHKPSNT KVDKTVERKC CVECPPCPAP PVAGPSVFLF PPKPKDTLMI SRTPEVTCW VDVSHEDPEV QFNWYVDGVE VHNAKTKPRE EQFNSTFRW SVLTWHQDW LNGKEYKCKV SNKGLPAPIE KTISKTKGQP |
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REPQVYTDPP SREEMTKNQV SDTCLVKGFY PSDIAVEWES NGQPENNYKT TPPMLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPG | ||
SEQ ID NO: 8 | Heavy Chain, Variable Domain | EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYWMHWVRQA PGKGLEWVSD IARLSSYTNY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARGL DARRMDYWGQ GTLVTVSS |
SEQ ID NO: 9 | Heavy Chain, Variable Domain, CDR1 | FSSYWMHW |
SEQ ID NO: 10 | Heavy Chain, Variable Domain, CDR2 | SDIARLSSYT NYADSVKGR |
SEQ ID NO: 11 | Heavy Chain, Variable Domain, CDR3 | ARGLDARRMD Y |
SEQ ID NO: 12 | Heavy Chain, Constant Domain | ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL MISRTPEVTC VWDVSHEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTFR WSVLTWHQ DWLNGKEYKC KVSNKGLPAP IEKTISKTKG QPREPQVYTL PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPMLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPG |
Thus, the present disclosure provides anti-PRLR mAb formulations, including anti-PRLR IgG2 mAb formulations, wherein the anti-PRLR mAb is soluble at high protein concentrations. Typically, the anti-PRLR mAh in the formulations disclosed herein remain soluble at concentrations from about 1 mg/ml to about 150 mg/ml and remain stable under isosmotic storage conditions and exhibit reduced viscosity as compared to currently available antibody formulations.
The anti-PRLR antibody having a light chain sequence and a heavy chain sequence presented in the Sequence Listing attached hereto and in one or more of PCT Patent Publication NOs. WO/2011/069799 (U.S. 2013/0129739),
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WO/2011/069798 (U.S. 2013/0022606), WO/2011/069797 (U.S. 2012/0315276), WO/2011/069796 (U.S. 2013/0171147), WO/2011/069795/ and WO/2011/069794 (U.S. 2012/0321632) can be an IgG2 antibody that blocks a prolactin receptor activity. Anti-PRLR antibodies can prevent the onset or progression of endometriosis by blocking PRLR, thereby overcoming deficiencies in endometrial pathways. The wide protein concentration range, including high concentration anti-PRLR antibody formulations presented herein can be administrated to the patients via intravenous injection intramuscular injection or subcutaneous injection.
The present disclosure also provides methods for the non-hormonaf treatment 10 of endometriosis in a patient, comprising the administration to the patient of a therapeutically effective amount of one or more formulations described herein. For example, provided are methods for the non-hormonal treatment of endometriosis in a patient, comprising the administration to the patient of a therapeutically effective amount of an anti-prolactin receptor antibody (aPRLR Ab) formulation including an aPRLR-specific IgG2 monocional antibody (mAh) formulation that contains from about 0 mM to about 70 mM histidine; from about 50 ppm to about 300 ppm polysorbate (Tween®) 80 and/or polysorbate (Tween®) 20; from about 34 mM to about 292 mM sucrose; from about 0 mM to about 50 mM arginine, from about 0 mM to about 50 mM lysine, from about 0 mM to about 270 mM glycine or alanine, from about 0 mM to about 10 mM methionine, and from about 1 mg/ml to about 150 mg/ml of an anti-PRLR antibody at a pH ranging from about pH 5.0 to about pH 6.5. Within at least one aspect of these methods, the anti-PRLR antibody formulation can be administered intravenously. Within other aspects of these methods, the antiPRLR antibody formulation can be administered subcutaneously. Within other aspects of these methods, the anti-PRLR antibody formulation can be administered intramuscularly.
According to certain aspects of these methods for the non-hormonal treatment of endometriosis in a patient, the anti-PRLR antibody is a human anti-PRLR IgG2 monoclonal antibody such as, for example, a human anti-PRLR IgG2 monoclonal antibody that contains a light chain sequence and a heavy chain sequence presented in one or more of PCT Patent Publication NOs. WO/2011/069799,
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WO/2011/069798, WO/2011/069797, WO/2011/069796, WO/2011/069795, and WO/2011/069794.
Aspects of the present disclosure may be further understood in light of the following examples, which should not be construed as limiting the scope of the present teachings in any way.
EXAMPLES
Example 1
Effect of NaCl Concentration and pH on the Turbidity of Antibody Solutions
This Example discloses the effect of salt (NaCl) concentration and pH on the aggregation of solutions containing an anti-PRLR human monoclonal antibody that contains a light chain sequence and a heavy chain sequence presented in one or more of PCT Patent Publication Nos. WO/2011/069799, WO/2011/069798,
WO/2011/069797, WO/2011/069796, WO/2011/069795, and WO/2011/069794.
The turbidity of solutions is assessed by visual observation to quickly evaluate the effects of salt concentrations and pH on aPRLR mAh solutions. No precipitation is observed after 2 months at 5 °C and 25 °C with the formulation in absence of salt at pH 5.5-6.5.
Solutions without sodium chloride at pH 5.0 to 6.5 are recommended for the presently disclosed anti-PRLR antibody formulations.
Without being bound by theory, it is believed that the decreased stability in terms of turbidity or aggregation of the anti-PRLR mAb formulations with high NaCl concentration results from the neutralization of positive charges on the anti-PRLR mAb arginine side-chains. The phase behavior of aPRLR mAb at different pH with the impact of monovalent salt (NaCl) explains why the stable, soluble, non-sait, and substantial isosmolality aPRLR mAb formulations are achieved.
At a pH below the PI, such as pH 5-6.5, an anti-PRLR antibody has a net positive charge. The repulsion of the positive charges on such an anti-PRLR antibody surface likely prevents protein-protein association between individual molecules and, thereby, significantly increases solubility. It is hypothesized that the 19
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Example 2
Anti-PRLR Antibody Formulations
Substantially isosmotic high concentration anti-PRLR Ab formulations are prepared without NaCl. These formulations employ high sucrose concentrations to help stabilize the anti-PRLR Ab,
Frozen anti-PRLR antibody is thawed and formulated according to formulations presented in Table 2. The formulations are prepared and are sterile filtered with a 0.22 pm filter and sterile filled in glass tubing vials and stoppered with rubber stoppers.
In the absence of NaCl, and in the presence of sucrose or trehalose 34 mM to 292 mM and polysobate 80 (50-300 ppm), and at pH 5.0-6.5, the positive charged amino acids, such as arginine (10-50 mM), can effectively inhibit aPRLR Ab from aggregation.
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Table 2
Anti-PRLR Antibody Formulations
1 mg/ml aPRLR Ab | ||
1 mg/ml aPRLR Ab 10 mM histidine 205 mM sucrose 75 ppm polysorbate 80 20 mM arginine 10 mM methionine pH 5.5 | ||
2 mg/ml aPRLR Ab | ||
2 mg/ml aPRLR Ab 10 mM histidine 234 mM sucrose 75 ppm polysorbate 80 30 mM arginine 10 mM methionine pH 5.5 | 2 mg/ml aPRLR Ab 10 mM histidine 234 mM sucrose 75 ppm polysorbate 80 30 mM arginine 10 mM methionine pH 5.0 | |
7.5 mg/ml aPRLR Ab | ||
7.5 mg/ml aPRLR Ab 10 mM histidine 234 mM sucrose 80 ppm polysorbate 80 30 mM arginine 5 mM methionine pH 5.5 | ||
20 mg/ml aPRLR Ab | ||
20 mg/ml aPRLR Ab 30 mM histidine 292 mM sucrose 60 ppm polysorbate 80 pH 5.0 | 20 mg/ml aPRLR Ab 30 mM histidine 292 mM sucrose 60 ppm polysorbate 80 pH 5.5 | 20 mg/ml aPRLR Ab 30 mM histidine 10% sucrose 60 ppm polysorbate 80 pH 6.5 |
20 mg/ml aPRLR Ab 30 mM histidine 292 mM sucrose 60 ppm polysorbate 80 50 mM arginine pH 6.0 | ||
50 mg/ml aPRLR Ab | ||
50 mg/ml aPRLR Ab 10 mM histidine 234 mM sucrose 75 ppm polysorbate 80 50 mM arginine pH at 6 | 50 mg/ml aPRLR Ab 10 mM histidine 234 mM sucrose 75 ppm polysorbate 80 30 mM arginine pH 5.5 | |
60 mg/ml aPRLR Ab | ||
60 mg/ml aPRLR Ab 10 mM histidine 234 mM sucrose 75 ppm polysorbate 80 pH 5.5 | 60 mg/ml aPRLR Ab 10 mM histidine 88 mM sucrose 200 ppm polysorbate 20 30 mM arginine 133 mM glycine pH at 5.5 | 60 mg/ml aPRLR Ab 10 mM histidine 205 mM sucrose 75 ppm polysorbate 80 20 mM arginine 10 mM methionine pH 6.5 |
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60 mg/ml aPRLR Ab 10 mM histidine 234 mM sucrose 75 ppm polysorbate 80 30 mM arginine pH 5.5 | 60 mg/ml aPRLR Ab 10 mM histidine 88 mM sucrose 75 ppm polysorbate 80 10 mM arginine 133 mM glycine pH 5.5 | 60 mg/ml aPRLR Ab 10 mM histidine 205 mM trehalose 75 ppm polysorbate 80 20 mM arginine 10 mM methionine pH 5.5 |
60 mg/ml aPRLR Tib 10 mM histidine 234 mM sucrose 75 ppm polysorbate 80 30 mM arginine pH 6, | 60 mg/ml aPRLR Ab 10 mM histidine 292 mM sucrose 75 ppm polysorbate 80 10 mM arginine 10 mM methionine 133 mM glycine pH 5.5 | 60 mg/ml aPRLR Ab 10 mM histidine 205 mM trehalose 75 ppm polysorbate 80 20 mM arginine 10 mM methionine pH 5.5 |
60 mg/ml aPRLR Ab 10 mM histidine 88 mM sucrose 75 ppm polysorbate 80 30 mM arginine 133 mM glycine pH 5.5 | 60 mg/ml aPRLR Ab 10 mM histidine 388 mM sucrose 75 ppm polysorbate 80 30 mM lysine 133 mM glycine pH 5,5 | 60 mg/mL aPRLR Ab 10 mM histidine 234 mM sucrose 80 ppm polysorbate 80 30 mM arginine 5 mM methionine pH 5.5 |
60 mg/ml aPRLR Ab 10 mM histidine 88 mM sucrose 75 ppm polysorbate 20 30 mM arginine 133 mM glycine pH 5.5 | 60 mg/ml aPRLR Ab 10 mM histidine 234 mM sucrose 75 ppm polysorbate 80 30 mM arginine 10 mM methionine pH 5.5 | 60 mg/mL aPRLR Ab 10 mM histidine 234 mM sucrose 75 ppm polysorbate 80 30 mM arginine 10 mM methionine pH 5.5 |
60 mg/mL aPRLR Ab 70 mM histidine 200 mM sucrose 80 ppm polysorbate 80 pH 6.0 | 60 mg/mL aPRLR Ab 10 mM histidine 263 mM sucrose 80 ppm polysorbate 80 pH 6.0 | 60 mg/mL aPRLR Ab 70 mM histidine 176 mM sucrose 75 ppm polysorbate 80 30 mM lysine pH 6.0 |
150 mg/ml aPRLR Ab | ||
150 mg/ml aPRLR Ab 10 mM histidine 234 mM sucrose 75 ppm polysorbate 80 30 mM arginine 10 mM methionine pH 5.5 |
Representative anti-PRLR mAb formulations were analyzed by HPLC-SEC for protein aggregation and degradation, LC-MS for aPRLR structural changes (glycation and oxidation), viscometer for viscosity measurement, and osmolality instrument for osmolality measurement. The results for the HPLC-SEC analysis of protein aggregation are presented in Table 3, the results for the nephlometry analysis of turbidity are presented in Table 4, the results for the LC-MS analysis of aPRLR structural changes are presented in Table 5, and the results for the analysis of viscosity and osmolality are presented in Table 6.
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Table 3
HPLC-SEC Average Rate of Aggregation Formation (%/dav)
Formulation Composition | 5°C | 25°C | |
Anti-PRLR Histidine Sucrose Polysorbate 80 PH Arginine Methionine | 60 mg/mL 10 mM 234 mM 75 ppm 5.5 30 mM 10 mM | 0.000 1 | 0.005 1 |
Anti-PRLR Histidine Sucrose Polysorbate 80 pH | 6 0 mg/mL 10 mM 263 mM 80 ppm 6.0 | 0.013 2 | 0.022 2 |
1 The calculation was based on 100 days value.
2 The calculation was based on 90 days value.
Table 4
LC-MS Results of the Formulations after Shaking at 100 rpm at Room Temperature
Formulation Composition | Intact Mass | Mass of LC and HC |
Anti-PRLR 60 mg/mL Histidine 10 mM Sucrose 234 mM Polysorbate 80 75 ppm pH 5.5 Arginine 30 mM Methionine 10 mM | Comparable to RS 1 | Comparable to RS 1 |
Anti-PRLR 60 mg/mL Histidine Ϊ0 mM Sucrose 263 mM Polysorbate 80 80 ppm pH 6.0 | Comparable to RS 2 | Comparable to RS 2 |
1 After the formulation was shaken at 100 rpm at room temperature for 14 days.
2 After the formulation was shaken at 100 rpm at room temperature for 21 days. LC = Light Chain; HC = Heavy Chain; RS = Reference Standard.
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Table 5
Average Rate of Turbidity change (by Nephelometry) After Shaking at 100 rpm at Room Temperature
Formulation Composition
Anti-PRLR | 60 | mg/mL | |
Histidine | 10 | mM | |
Sucrose | 234 | mM | |
Polysorbate | 80 | 75 | PPm |
PH | 5 | 5 | |
Arginine | 30 | mM | |
Methionine | 10 | mM | |
Anti-PRLR | 60 | mg/mL | |
Histidine | 10 | mM | |
Sucrose | 263 | mM | |
Polysorbate | 80 | 80 | PPm |
PH | 6 | 0 |
FNU/day
0.643 1
0.013 1 After the formulation was shaken at 100 rpm at room temperature for 14 days. 5 2 After the formulation was shaken at 100 rpm at room temperature for 21 days.
Table 6
Viscosity and Osmolality of Anti-PRLR Ab Formulations
Formulation | Composition | Viscosity (mPa-S) at 22.0°C-23.0°C | Osmolality (mmol/kg) |
Ant i-PRLR | 60 mg/mL | ||
Histidine | 10 mM | ||
Sucrose | 234 mM | ||
Polysorbate 80 | 80 ppm | 1.83 | 342 |
PH | 5.5 | ||
Arginine | 3 0 mM | ||
Methionine | 5 mM | ||
Anti-PRLR | 60 mg/mL | ||
Histidine | 10 mM | ||
Sucrose | 234 mM | ||
Polysorbate 80 | 75 ppm | 2.37 | 345 |
PH | 5.5 | ||
Arginine | 3 0 mM | ||
Methionine | 10 mM | ||
Anti-PRLR | 60 mg/mL | ||
Histidine | 10 mM | ||
Sucrose | 263 mM | 2.17 | 299 |
Polysorbate 80 | 80 ppm | ||
PH | 6.0 |
2013308907 21 Dec 2017
Throughout this specification and the claims which follow, unless the context requires otherwise, the word comprise, and variations such as comprises or comprising, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
24A
2013308907 21 Dec 2017
Claims (27)
- The claims defining the invention are as follows:1. An anti-PRLR antibody formulation, comprising:10 mM to 70 mM histidine;50 ppm to 300 ppm polysorbate 80;34 mM to 292 mM sucrose; and1 mg/ml to 150 mg/ml of an anti-PRLR antibody; wherein said anti-PRLR antibody formulation has a pH ranging from pH 5.0 to pH 6.5, and wherein the formulation comprises substantially no salt other than an organic or inorganic salt that buffers said formulation.
- 2. The anti-PRLR antibody formulation of claim 1, comprising:10 mM histidine,80 ppm polysorbate 80,234 mM sucrose,60 mg/ml anti-PRLR antibody.
- 3. The anti-PRLR antibody formulation of claim 1, comprising:10 mM histidine,75 ppm polysorbate 80,234 mM sucrose, and 60 mg/ml anti-PRLR antibody.
- 4. The anti-PRLR antibody formulation of claim 1, comprising:10 mM histidine,80 ppm polysorbate 80,263 mM sucrose, and 60 mg/ml anti-PRLR antibody.
- 5. The anti-PRLR antibody formulation of claim 1, comprising:30 mM histidine,100 ppm polysorbate 80,292 mM sucrose, and2013308907 21 Dec 201720 mg/ml anti-PRLR antibody.
- 6. The anti-PRLR antibody formulation of claim 1, comprising:70 mM histidine,80 ppm polysorbate 80,200 mM sucrose, and 60 mg/ml anti-PRLR antibody.
- 7. The anti-PRLR antibody formulation of any one of claims 1 to 6, further comprising 133 to 270 mM glycine.
- 8. The anti-PRLR antibody formulation of claim 7, comprising:10 mM histidine,75 ppm polysorbate 80,88 mM sucrose,270 mM glycine, and 60 mg/ml anti-PRLR antibody.
- 9. The anti-PRLR antibody formulation of claim 7, comprising:
- 10 mM histidine,75 ppm polysorbate 20,88 mM sucrose,133 mM glycine, and 60 mg/ml anti-PRLR antibody.10. The anti-PRLR antibody formulation of claim 7, comprising:10 mM histidine,200 ppm polysorbate 20,88 mM sucrose,133 mM glycine, and 60 mg/ml anti-PRLR antibody.2013308907 21 Dec 2017
- 11. The anti-PRLR antibody formulation of claim 7, comprising:10 mM histidine,75 ppm polysorbate 80,292 mM sucrose,270 mM glycine, and 60 mg/ml anti-PRLR antibody.
- 12. The anti-PRLR antibody formulation of any one of claims 1 to 11, further comprising:10 to 50 mM arginine;5 to 10 mM methionine; or10 to 50 mM arginine and 10 to 50 mM methionine.
- 13. The anti-PRLR antibody formulation of claim 12, comprising:10 mM histidine,75 ppm polysorbate 80,292 mM sucrose,10 mM arginine, and 60 mg/ml anti-PRLR antibody.
- 14. The anti-PRLR antibody formulation of claim 12, comprising:10 mM histidine,75 ppm polysorbate 80,234 mM sucrose,30mM arginine, and lOmM methionine, and 60 mg/ml anti-PRLR antibody.
- 15. The anti-PRLR antibody formulation of claim 12, comprising:10 mM histidine,75 ppm polysorbate 80,234 mM sucrose,2013308907 21 Dec 201730 mM arginine, and 10 mM methionine, and 2 mg/ml anti-PRLR antibody.
- 16. The anti-PRLR antibody formulation of claim 12, comprising: 10 mM histidine,75 ppm polysorbate 80,234 mM sucrose,20 mM arginine, and 10 mM methionine, and 150 mg/ml anti-PRLR antibody.
- 17. The anti-PRLR antibody formulation of claim 12, comprising: 10 mM histidine,75 ppm polysorbate 80,205 mM sucrose,20 mM arginine,10 mM methionine, and 1 mg/ml anti-PRLR antibody.
- 18. The anti-PRLR antibody formulation of claim 12, comprising: 10 mM histidine,80 ppm polysorbate 80,205 mM sucrose,20 mM arginine, and 10 mM methionine, and 60 mg/ml anti-PRLR antibody.
- 19. The anti-PRLR antibody formulation of claim 12, comprising: 10 mM histidine,234 mM sucrose,80 ppm polysorbate 80,2013308907 21 Dec 201730 mM arginine,5 mM methionine, and7.5 mg/ml anti-PRLR antibody.
- 20. The anti-PRLR antibody formulation of claim 12, comprising:10 mM histidine,234 mM sucrose,80 ppm polysorbate 80,30 mM arginine,5 mM methionine, and 60 mg/mL anti-PRLR antibody.
- 21. The anti-PRLR antibody formulation of claim 12, comprising:10 mM histidine,234 mM sucrose,75 ppm polysorbate 80,30 mM arginine,10 mM methionine, and 60 mg/mL anti-PRLR antibody.
- 22. The anti-PRLR antibody formulation of any one of claims 1 to 21, further comprising 30 to 50 mM lysine.
- 23. The anti-PRLR antibody formulation of claim 22, comprising:70 mM histidine,75 ppm polysorbate 80,176 mM sucrose,30 mM lysine, and60 mg/ml anti-PRLR antibody.
- 24. The anti-PRLR antibody formulation of any one of claims 1 to 23, further comprising 34 to 292 mM trehalose.2013308907 05 Mar 2018
- 25. The anti-PRLR antibody formulation of claim 24, comprising:10 mM histidine,75 ppm polysorbate 80,205 mM trehalose,30 mM arginine,10 mM methionine, and 2 mg/ml anti-PRLR antibody.
- 26. The anti-PRLR antibody formulation of claim 24, comprising:10 mM histidine,75 ppm polysorbate 80,205 mM trehalose,20 mM arginine, and 10 mM methionine, and 60 mg/ml anti-PRLR antibody.
- 27. The anti-PRLR antibody formulation of any one of claims 1 to 26, wherein said anti-PRLR antibody is a human IgG2 monoclonal antibody comprising a light chain sequence of SEQ ID NO: 1 and a heavy chain sequence of SEQ ID NO:7.2013-08-28-SEQUENCE-LISTING.TXT SEQUENCE LISTING <110> Bayer Healthcare LLC Ma, Xinghang Xiang, Jun Niu, Jianjie <120> ANTI-PROLACTIN RECEPTOR ANTIBODY FORMULATIONS <130> 17207.0001WOU1 <140> To Be Assigned <141> 2013-08-28 <150> US 13/842,906 <151> 2013-03-15 <150> 61/695,949 <151> 2012-08-31 <160> 60 <170> PatentIn version 3.5 <210> 1 <211> 217 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(217) <223> Anti-Prolactin MAb -- Light Chain, Full-length <400> 1
Gln Ser 1 Val Leu Thr 5 Gln Pro Pro Ser Ala Ser 10 Gly Thr Pro Gly 15 Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Val Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser 85 90 95 Leu Asn Gly Trp Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 115 120 125Page 12013-08-28-SEQUENCE-LISTING.TXTGlu Leu 130 Gln Ala Asn Lys Ala 135 Thr Leu Val Cys Leu 140 Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 145 150 155 160 Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185 190 His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 195 200 205 Lys Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> 2 <211> 113 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(113) <223> Anti-Prolactin MAb -- Light Chain, Variable Domain <400> 2Gln 1 Ser Val Leu Thr 5 Gln Pro Pro Ser Ala Ser Gly Thr 10 Pro Gly 15 Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Val Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser 85 90 95 Leu Asn Gly Trp Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110GlnPage 22013-08-28-SEQUENCE-LISTING.TXT <210> 3 <211> 16 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(16) <223> Anti-Prolactin MAb -- Light Chain, Variable Domain, CDR1 <400> 3Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Val Val His 1 5 10 15 <210> 4 <211> 7 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(7) <223> Anti-Prolactin MAb -- Light Chain, Variable Domain, CDR2 <400> 4Arg Asn Asn Gln Arg Pro Ser1 5 <210> 5 <211> 12 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(12) <223> Anti-Prolactin MAb -- Light Chain, Variable Domain, CDR3 <400> 5Cys Ala Ala Trp Asp Asp Ser Leu Asn Gly Trp Leu1 5 10 <210> 6 <211> 104 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(84) <223> Anti-Prolactin MAb -- Light Chain, Constant Domain <400> 6Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 1 5 10 15Page 32013-08-28-SEQUENCE-LISTING.TXTLeu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 20 25 30 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 35 40 45 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 50 55 60 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 65 70 75 80 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 85 90 95 Thr Val Ala Pro Thr Glu Cys Ser 100 <210> <211> <212> <213> 7 443 PRT Homo sapiens <220> <221> MISC FEATURE <222> (1).. (443) <223> Anti- -Prolactin MAb -- Heavy Chain, Full-length <400> 7 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu Ser Cys 20 Ala Ala Ser Gly Phe 25 Thr Phe Ser 30 Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ala Arg Leu Ser Ser Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Leu Asp Ala Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Page 4115 2013-08-28-SEQUENCE-LISTING.TXT 120 125 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 210 215 220 Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe 260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 290 295 300 Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Page 5 4003852013-08-28-SEQUENCE-LISTING.TXT 390 395Phe Phe Leu Tyr Ser 405 Lys Leu Thr Val Asp 410 Lys Ser Arg Trp Gln 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 <210> 8 <211> 118 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(118) <223> Anti-Prolactin MAb -- Heavy Chain, Variable Domain <400> 8Glu 1 Val Gln Leu Leu 5 Glu Ser Gly Gly Gly 10 Leu Val Gln Pro Gly 15 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ala Arg Leu Ser Ser Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Leu Asp Ala Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 9 <211> 8 <212> PRT <213> Homo sapiens <220> <221> MISC_FEATURE Page 62013-08-28-SEQUENCE-LISTING.TXT <222> (1)..(8) <223> Anti-Prolactin MAb -- Heavy Chain, Variable Domain, CDR1 <400> 9Phe Ser Ser Tyr Trp Met His Trp1 5<210> 10 <211> 19 <212> PRT <213> Homo sapiens <220> <221> MISC FEATURE <222> (1). (19) <223> Anti -Prolactin MAb -- Heavy Chain , Variable Domain, CDR2 <400> 10 Ser Asp Ile Ala Arg Leu Ser Ser Tyr Thr Asn Tyr Ala Asp Ser Val 1 5 10 15 Lys Gly Arg <210> 11 <211> 11 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(11) <223> Anti-Prolactin MAb -- Heavy Chain, Variable Domain, CDR3 <400> 11Ala Arg Gly Leu Asp Ala Arg Arg Met Asp Tyr1 5 10<210> 12 <211> 325 <212> PRT <213> Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (325) <223> Anti- Prolactin MAb -- Heavy Chain , Constant Domain <400> 12 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Page 72013-08-28-SEQUENCE-LISTING.TXTPhe Pro Glu 35 Pro Val Thr Val Ser 40 Trp Asn Ser Gly Ala Leu Thr Ser 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro 100 105 110 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140 Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 165 170 175 Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205 Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu 210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 245 250 255 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 260 265 270 Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 275 280 285 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 290 295 300 Page 82013-08-28-SEQUENCE-LISTING.TXTSer Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 305 310 315 320Ser Leu Ser Pro Gly 325<210> 13 <211> 118 <212> PRT <213> Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (118) <223> Anti- -Prolactin (aPRLR) Ab 005-C04 -- Variable Heavy Chain <400> 13 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu 20 Ser Cys Ala Ala Ser Gly Phe 25 Thr Phe Ser 30 Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Ser Ala Ser Ser Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Leu Asp Ala Arg Arg Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 14 <211> 113 <212> PRT <213> Homo sapiens <220> <221> MISC_FEATURE <222> (1)..(113) <223> Anti-Prolactin (aPRLR) Ab 005-C04 -- Variable Light Chain <400> 14Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15Page 92013-08-28-SEQUENCE-LISTING.TXTArg Val Thr Ile 20 Ser Cys Thr Gly Ser 25 Ser Ser Asn Ile Gly 30 Ala Gly Tyr Val Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser 85 90 95 Leu Asn Gly Trp Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 Gln <210> 15 <211> 8 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(8) <223> Anti-Prolactin (aPRLR) Ab 005-C04 -- Variable heavy chain CDR1 <400> 15Phe Ser Ser Tyr Trp Met His Trp1 5 <210> 16 <211> 19 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(19) <223> Anti-Prolactin (aPRLR) Ab 005-C04 -- Variable heavy chain CDR2 <400> 16Ser Asp Ile Ser Ser Ala Ser Ser Tyr Thr Asn Tyr Ala Asp Ser Val 1 5 10 15Lys Gly ArgPage 102013-08-28-SEQUENCE-LISTING.TXT<210> 17 <211> 11 <212> PRT <213> Homo sapiens <220> <221> MISC_FEATURE <222> (1)..(11) <223> Anti-Prolactin (aPRLR) Ab 005-C04 -- Variable heavy chain CDR3 <400> 17 Ala Arg Gly Leu Asp Ala Arg Arg Met Asp Tyr 1 5 10 <210> 18 <211> 14 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(14) <223> Anti-Prolactin (aPRLR) Ab 005-C04 -- Variable light chain CDR1<400> Thr Gly 1 18 Ser Ser Ser Asn Ile Gly Ala Gly Tyr Val Val His 5 10 <210> 19 <211> 7 <212> PRT <213> Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (7) <223> Anti- -Prolactin (aPRLR) Ab 005 -C04 -- Variable light chain CDR2 <400> 19 Arg Asn Asn Gln Arg Pro Ser 1 5 <210> 20 <211> 11 <212> PRT <213> Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (11) <223> Anti- -Prolactin (aPRLR) Ab 005-C04 -- Variable light chain CDR3 <400> 20 Cys Ala Ala Trp Asp Asp Ser Leu Asn Gly Trp 1 5 10Page 112013-08-28-SEQUENCE-LISTING.TXT <210> 21 <211> 119 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(119) <223> Anti-Prolactin (aPRLR) Ab 002-H06 -- Variable Heavy Chain <400> 21Gln Val 1 Glu Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 15 Gly 5 10 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asn Tyr 20 25 30 Gly Leu Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Phe Asn Gly Asp Lys Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Pro Leu Glu Ser Pro Val Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 22 <211> 112 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(112) <223> Anti-Prolactin (aPRLR) Ab 002-H06 -- Variable Light Chain <400> 22Gln Ser Val 1 Leu Thr Gln 5 Pro Pro Ser Ala Ser 10 Gly Thr Pro Gly 15 Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Tyr Ser Asn Ile Gly Gly Asn 20 25 30 Pro Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45Page 122013-08-28-SEQUENCE-LISTING.TXTIle Tyr 50 Gly Asn Ser Asn Arg 55 Pro Ser Gly Val Pro 60 Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95Ser Gly Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 <210> 23 <211> 8 <212> PRT <213> Homo sapiens <220> <221> MISC FEATURE <222> (1). (8) <223> Anti Prolactin (aPRLR) Ab 002-H06 -- Variable heavy chain CDR1 <400> 23 Phe Ala Asn Tyr Gly Leu Thr Trp 1 5 <210> 24 <211> 19 <212> PRT <213> Homo sapiens <220> <221> MISC FEATURE <222> (1). (19) <223> Anti -Prolactin (aPRLR) Ab 002-H06 -- Variable heavy chain CDR2 <400> 24 Ala Val Ile Ser Phe Asn Gly Asp Lys Lys Tyr Tyr Ala Asp Ser Val 1 5 10 15 Lys Gly Arg <210> 25 <211> 12 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(12) <223> Anti-Prolactin (aPRLR) Ab 002-H06 -- Variable heavy chain CDR3 <400> 25Page 132013-08-28-SEQUENCE-LISTING.TXTAla Ser Pro Leu Glu Ser Pro Val Ala Phe Asp Ile 1 5 10 <210> 26 <211> 13 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(13) <223> Anti-Prolactin (aPRLR) Ab 002-H06 -- Variable light chain CDR1 <400> 26Ser Gly Ser Tyr Ser Asn Ile Gly Gly Asn Pro Val Asn1 5 10 <210> 27 <211> 7 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(7) <223> Anti-Prolactin (aPRLR) Ab 002-H06 -- Variable light chain CDR2 <400> 27Gly Asn Ser Asn Arg Pro Ser1 5 <210> 28 <211> 11 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(11) <223> Anti-Prolactin (aPRLR) Ab 002-H06 -- Variable light chain CDR3 <400> 28Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Ser1 5 10 <210> <211> <212> <213> 29 115 PRT Homo sapiens <220> <221> <222> <223> MISC_ (1).. Anti- FEATURE (115) Prolactin (aPRLR) Ab 002-H08 -- Variable Heavy Chain <400> 29 Page 142013-08-28-SEQUENCE-LISTING.TXTGln 1 Val Glu Leu Leu 5 Glu Ser Gly Gly Gly 10 Leu Val Gln Pro Gly 15 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Val Ser Trp Asn Gly Ser Arg Thr His Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Leu Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 30 <211> 113 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(113) <223> Anti-Prolactin (aPRLR) Ab 002-H08 -- Variable Light Chain <400> 30Gln 1 Ser Val Leu Thr Gln 5 Pro Pro Ser Ala Ser Gly 10 Thr Pro Gly 15 Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Asp Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95Page 152013-08-28-SEQUENCE-LISTING.TXTSer Gly Ser Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 Gln <210> 31 <211> 8 <212> PRT <213> Homo sapiens <220> <221> MISC_FEATURE <222> (1)..(8) <223> Anti-Prolactin (aPRLR) Ab 002 -H08 -- Variable heavy chain CDR1 <400> 31 Phe Ser Ser Tyr Gly Met His Trp 1 5 <210> 32 <211> 19 <212> PRT <213> Homo sapiens <220> <221> MISC_FEATURE <222> (1)..(19) <223> Variable heavy chain CDR2 <400> 32 Ser Gly Val Ser Trp Asn Gly Ser Arg Thr His Tyr Ala Asp Ser Val 1 5 10 15 Lys Gly Arg <210> 33 <211> 9 <212> PRT <213> Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (9) <223> Anti- Prolactin (aPRLR) Ab 002-H08 -- Variable heavy chain CDR3 <400> 33 Cys Ala Arg Gly Gly Asp Phe Asp Tyr 1 5 <210> 34 <211> 13 <212> PRTPage 162013-08-28-SEQUENCE-LISTING.TXT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(13) <223> Anti-Prolactin (aPRLR) Ab 002-H08 -- Variable light chain CDR1 <400> 34Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Asp Val Tyr1 5 10 <210> <211> <212> <213> 35 7 PRT Homo sapiens <220> <221> <222> <223> MISC_ (1).. Anti- FEATURE (7) Prolactin (aPRLR) Ab 002-H08 -- Variable light chain CDR2 <400> 35 Asp Asn Asn Lys Arg Pro Ser 1 5 <210> 36 <211> 12 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(12) <223> Anti-Prolactin (aPRLR) Ab 002-H08 -- Variable light chain CDR3 <400> 36Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Ser Trp1 5 10 <210> 37 <211> 119 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(119) <223> Anti-Prolactin (aPRLR) Ab 006-H07 -- Variable Heavy Chain<400> 37 Gln Val Glu Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Asp His 20 25 30 Page 172013-08-28-SEQUENCE-LISTING.TXTGly Met Ser Trp 35 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 40 45 Ser Leu Ile Ser Trp Asp Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser 50 55 60 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 65 70 75 80 Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Thr Ser Leu Arg Ala Thr Ala Phe Asp Thr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 38 <211> 112 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(112) <223> Anti-Prolactin (aPRLR) Ab 006-H07 -- Variable Light Chain <400> 38Gln 1 Ser Val Leu Thr Gln 5 Pro Pro Ser Ala Ser Gly 10 Thr Pro Gly 15 Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 <210> 39 <211> 8Page 182013-08-28-SEQUENCE-LISTING.TXT <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(8)<223> <400> Phe Glu 1 Anti-Prolactin (aPRLR) Ab 006-H07 -39 Asp His Gly Met Ser Trp 5 Variable heavy chain CDR1 <210> 40 <211> 20 <212> PRT <213> Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (20) <223> Anti- -Prolactin (aPRLR) Ab 006-H07 -- Variable heavy chain CDR2 <400> 40 Ser Leu Ile Ser Trp Asp Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser 1 5 10 15 Val Lys Gly Arg 20 <210> 41 <211> 11 <212> PRT <213> Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (11) <223> Anti- -Prolactin (aPRLR) Ab 006-H07 -- Variable heavy chain CDR3 <400> 41 Ala Thr Ser Leu Arg Ala Thr Ala Phe Asp Thr 1 5 10 <210> 42 <211> 13 <212> PRT <213> Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (13) <223> Anti- -Prolactin (aPRLR) Ab 006-H07 -- Variable light chain CDR1 <400> 42 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Ala Val Asn 1 5 10Page 192013-08-28-SEQUENCE-LISTING.TXT<210> 43 <211> 7 <212> PRT <213> Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (7) <223> Anti- Prolactin (aPRLR) Ab 006-H07 -- Variable light chain CDR2 <400> 43Ser Asn Asn Gln Arg Pro Ser 1 5 <210> 44 <211> 11 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(11) <223> Anti-Prolactin (aPRLR) Ab 006-H07 -- Variable light chain CDR3 <400> 44Cys Ala Ala Trp Asp Asp Ser Leu Ser Gly Trp1 5 10 <210> 45 <211> 123 <212> PRT <213> Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (123) <223> Anti- Prolactin (aPRLR) Ab 001-E06 -- Variable Heavy Chain <400> 45Gln 1 Val Glu Leu Leu 5 Glu Ser Gly Gly Gly Leu Val 10 Gln Pro Gly 15 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Val Ser Asp Thr Gly Thr Asp Thr His Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Page 202013-08-28-SEQUENCE-LISTING.TXTLeu Gln Met Asn Ser Leu Arg Ala Glu Asp 90 Thr Ala Val Tyr Tyr 95 Cys 85 Ala Lys Thr Pro Leu Ala Tyr Ser Ser Gly Trp Tyr Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 46 <211> 112 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(112) <223> Anti-Prolactin (aPRLR) Ab 001-E06 -- Variable Light Chain <400> 46Asp 1 Ile Val Leu Thr Gln 5 Pro Pro Ser Ala Ser Gly 10 Thr Pro Gly 15 Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Tyr Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Ser Gly Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 <210> 47 <211> 8 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(8) <223> Anti-Prolactin (aPRLR) Ab 001-E06 -- Variable heavy chain CDR1 <400> 47Phe Ser Ser Tyr Trp Met Ser TrpPage 212013-08-28-SEQUENCE-LISTING.TXT<210> 48 <211> 19 <212> PRT <213> Homo sapiens <220> <221> MISC_FEATURE <222> (1)..(19) <223> Anti-Prolactin (aPRLR) Ab 001-E06 -- Variable heavy chain CDR2 <400> 48 Ser Ser Val Ser Asp Thr Gly Thr Asp Thr His Tyr Ala Asp Ser Val 1 5 10 15Lys Gly Arg<210> 49 <211> 15 <212> PRT <213> Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (15) <223> Anti- Prolactin (aPRLR) Ab 001-E06 -- Variable heavy chain CDR3 <400> 49 Ala Lys Thr Pro Leu Ala Tyr Ser Ser Gly Trp Tyr Tyr Phe Asp 1 5 10 15 <210> 50 <211> 13 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(13) <223> Anti-Prolactin (aPRLR) Ab 001-E06 -- Variable light chain CDR1 <400> 50Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn1 5 10 <210> 51 <211> 7 <212> PRT<213> Homo sapiens <220> <221> MISC_FEATURE <222> (1)..(7) <223> Anti-Prolactin (aPRLR) Ab 001-E06 -- Variable light chain CDR2 Page 22 2013-08-28-SEQUENCE-LISTING.TXT <400> 51Arg Asn Tyr Gln Arg Pro Ser 1 5 <210> 52 <211> 11 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(11) <223> Anti-Prolactin (aPRLR) Ab 001-E06 -- Variable light chain CDR3 <400> 52Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Ser1 5 10 <210> 53 <211> 119 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(119) <223> Anti-Prolactin (aPRLR) Ab 006-H08 -- Variable Heavy Chain <400> 53Gln Val 1 Glu Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 15 Gly 5 10 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Gln Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Pro Leu Glu Ser Pro Val Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Ile Val Ser Ser 115Page 232013-08-28-SEQUENCE-LISTING.TXT <210> 54 <211> 112 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(112) <223> Anti-Prolactin (aPRLR) Ab 006-H08 -- Variable Light Chain <400> 54Asp Ile Val 1 Leu Thr 5 Gln Pro Pro Ser Ala Ser Gly Thr 10 Pro Gly 15 Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Ile Gly Ser Asn 20 25 30 Pro Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Thr Gly Leu 85 90 95Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 <210> <211> <212> <213> 55 8 PRT Homo sapiens <220> <221> <222> MISC (1). FEATURE (8) <223> Anti-Prolactin (aPRLR) Ab 006-H08 -- Variable heavy chain CDR1 <400> 55Phe Asp Asp Tyr Gly Met Ser Trp1 5<210> <211> <212> <213> 56 19 PRT Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (19) Page 242013-08-28-SEQUENCE-LISTING.TXT<223> Anti-Prolactin (aPRLR) Ab 006-H08 -- Variable heavy chain CDR2 <400> 56 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 1 5 10 15 Lys Gly Arg <210> 57 <211> 12 <212> PRT <213> Homo sapiens <220><221> MISC_FEATURE <222> (1)..(12)<223> <400> Ala Ser 1 Anti-Prolactin (aPRLR) Ab 006-H08 -57 Pro Leu Glu Ser Pro Val Ala Phe Asp Variable Ile heavy chain CDR3 5 10 <210> 58 <211> 13 <212> PRT <213> Homo sapiens <220> <221> MISC_FEATURE <222> (1)..(13) <223> Anti-Prolactin (aPRLR) Ab 006-H08 -- Variable light chain CDR1 <400> 58Ser Gly Ser Asn Ser Asn Ile Gly Ser Asn Pro Val Asn1 5 10 <210> 59 <211> 7 <212> PRT <213> Homo sapiens <220> <221> MISC_ FEATURE <222> (1).. (7) <223> Anti- -Prolactin (aPRLR) Ab 006-H08 -- Variable light chain CDR2 <400> 59 Asp Asn Asn Lys Arg Pro Ser 1 5 <210> 60 <211> 11 <212> PRT <213> Homo sapi Page 252013-08-28-SEQUENCE-LISTING.TXT <220><221> MISC_FEATURE <222> (1)..(11) <223> Anti-Prolactin (aPRLR) Ab 006-H08 -- Variable light chain CDR3 <400> 60Cys Gln Ser Tyr Asp Thr Gly Leu Ser Gly Trp1 5 10Page 26
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